Biology subjects

Plas, S.

Publications and source records attributed to Plas, S..

2 recordsLinked to original sources

bioRxiv2025

Locus Coeruleus-Amygdala Circuit Disrupts Prefrontal Control to Impair Fear Extinction

BackgroundStress undermines extinction learning and hinders exposure-based clinical therapies for a variety of neuropsychiatric disorders. In both animals and humans, dysfunction in the ventromedial prefrontal cortex (vmPFC) contributes to stress-impaired extinction, but the neural circuit by which stress modulates vmPFC function is not known. We hypothesize that the locus coeruleus (norepinephrine system (LC-NE) undermines extinction learning by recruiting projections from the basolateral amygdala (BLA) to vmPFC. MethodsWe combined chemogenetics, calcium imaging, and fiber photometry to examine how the LC-NE system influences fear extinction, with special interest to LC[->]BLA projections. We infused viral vectors into the LC, BLA, and ventromedial prefrontal cortex (vmPFC) to express designer receptors (hM3Dq) or calcium indicators (GCaMP). The LC was globally or selectively (LC[->]BLA projections) stimulated, while vmPFC and BLA activity was monitored during different stages of memory processing. Intra-BLA propranolol infusions were used to block {beta}-adrenergic receptors to test their role in LC-driven effects. ResultsWe found that chemogenetic activation of the LC increased freezing behavior, suppressed vmPFC neuronal activity, and mimicked the effects of footshock. LC stimulation impaired both delayed and immediate extinction learning, while activation of the LC[->]BLA pathway alone was sufficient to drive the immediate extinction deficit. LC activation increased activity in BLA neurons projecting to vmPFC, and this effect, as well as vmPFC suppression, was prevented by {beta}-adrenergic blockade with propranolol in the BLA. Overall, LC-driven NE release in the BLA disrupted vmPFC activity and dynamics, promoted a high-stress stated and impaired fear extinction. ConclusionThis study demonstrates that stress and LC activation promote NE release in the BLA, which disrupts vmPFC activity and impairs fear extinction. These findings identify the LC-BLA-vmPFC circuit as a key pathway through which stress undermines extinction learning, highlighting BLA {beta}-adrenergic receptors as potential therapeutic targets for stress-related disorders like PTSD.

neuroscience↗

bioRxiv2024

Acute stress yields a sex-dependent facilitation of signaled active avoidance in rats

Post-traumatic stress disorder (PTSD) is a debilitating disorder characterized by excessive fear, hypervigilance, and avoidance of thoughts, situations or reminders of the trauma. Among these symptoms, relatively little is known about the etiology of pathological avoidance. Here we sought to determine whether acute stress influences avoidant behavior in adult male and female rats. We used a stress procedure (unsignaled footshock) that is known to induce long-term sensitization of fear and potentiate aversive learning. Rats were submitted to the stress procedure and, one week later, underwent two-way signaled active avoidance conditioning (SAA). In this task, rats learn to prevent an aversive outcome (shock) by performing a shuttling response when exposed to a warning signal (tone). We found that acute stress significantly enhanced SAA acquisition rate in females, but not males. Female rats exhibited significantly greater avoidance responding on the first day of training relative to controls, reaching similar levels of performance by the second day. Males that underwent the stress procedure showed similar rates of acquisition to controls but exhibited resistance to extinction. This was manifest as both elevated avoidance and intertrial responding across extinction days relative to non-stressed controls, an effect that was not observed in females. In a second experiment, acute stress sensitized footshock unconditioned responses in males, not females. However, males and females exhibited similar levels of stress-enhanced fear learning (SEFL), which was expressed as sensitized freezing to a shock-paired context. Together, these results reveal that acute stress facilitates SAA performance in both male and female rats, though the nature of this effect is different in the two sexes. We did not observe sex differences in SEFL, suggesting that the stress-induced sex difference in performance was selective for instrumental avoidance. Future work will elucidate the neurobiological mechanisms underlying the differential effect of stress on instrumental avoidance in male and female rats.

neuroscience↗